CXCR3+ T Follicular Helper Cells Induced by Co-Administration of RTS,S/AS01B and Viral-Vectored Vaccines Are Associated With Reduced Immunogenicity and Efficacy Against Malaria

Bowyer, Georgina; Grobbelaar, Amy; Rampling, Tommy; Venkatraman, Navin; Morelle, Danielle; Ballou, Ripley; Avs., Hill; Ewer, Katie

doi:10.3389/fimmu.2018.01660

Cited by 36 publications

(27 citation statements)

References 54 publications

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“…The successful combination of the two vaccines contrasts with previous studies where the combination of different viral vectored malaria vaccines did result in strong immune interference (23, 24) and the combination of RTS,S/AS01 with a viral vector PEV (ChAd63/MVA ME-TRAP) failed to improve vaccine efficacy when compared to the two vaccines administered individually and reduced immunogenicity and efficacy against malaria (25). This success might be attributed to shared characteristics and modes of action of RTS,S/AS01 and Pfs25-IMX313.…”

Section: Discussioncontrasting

confidence: 66%

Combination of RTS,S and Pfs25-IMX313 Induces a Functional Antibody Response Against Malaria Infection and Transmission in Mice

et al. 2018

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The last two decades saw a dramatic reduction in malaria incidence rates, but this decrease has been stalling recently, indicating control measures are starting to fail. An effective vaccine, particularly one with a marked effect on disease transmission, would undoubtedly be an invaluable tool for efforts to control and eliminate malaria. RTS,S/AS01, the most advanced malaria vaccine to date, targets the parasite before it invades the liver and has the potential to prevent malaria disease as well as transmission by preventing blood stage infection and therefore gametocytogenesis. Unfortunately efficacy in a phase III clinical trial was limited and it is widely believed that a malaria vaccine needed to contain multiple antigens from different life-cycle stages to have a realistic chance of success. A recent study in mice has shown that partially efficacious interventions targeting the pre-erythrocytic and the sexual lifecycle stage synergise in eliminating malaria from a population over multiple generations. Hence, the combination of RTS,S/AS01 with a transmission blocking vaccine (TBV) is highly appealing as a pragmatic and powerful way to increase vaccine efficacy. Here we demonstrate that combining Pfs25-IMX313, one of the TBV candidates currently in clinical development, with RTS,S/AS01 readily induces a functional immune response against both antigens in outbred CD1 mice. Formulation of Pfs25-IMX313 in AS01 significantly increased antibody titres when compared to formulation in Alhydrogel, resulting in improved transmission reducing activity in standard membrane feeding assays (SMFA). Upon co-formulation of Pfs25-IMX313 with RTS,S/AS01, the immunogenicity of both vaccines was maintained, and functional assessment of the induced antibody response by SMFA and inhibition of sporozoite invasion assay (ISI) showed no reduction in biological activity against parasites of both lifecycle stages. Should this findings be translatable to human vaccination this could greatly aid efforts to eliminate and eventually eradicate malaria.

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Section: Discussioncontrasting

confidence: 66%

Combination of RTS,S and Pfs25-IMX313 Induces a Functional Antibody Response Against Malaria Infection and Transmission in Mice

et al. 2018

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“…Using in vitro assays, it was also shown that this combination of vaccines exhibited similar functional activity in TB and sporozoite inhibition. Using in vivo assays, our results from mice immunized with the mixture of single-antigen formulations are in line with those of this previous study, in contrast with the studies that found immune interference or reduced efficacies for combinations of several other malaria vaccines (11, 41, 42).…”

Section: Discussionsupporting

confidence: 91%

A Viral-Vectored Multi-Stage Malaria Vaccine Regimen With Protective and Transmission-Blocking Efficacies

et al. 2019

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Malaria parasites undergo several stages in their complex lifecycle. To achieve reductions in both the individual disease burden and malaria transmission within communities, a multi-stage malaria vaccine with high effectiveness and durability is a more efficacious strategy compared with a single-stage vaccine. Here, we generated viral-vectored vaccines based on human adenovirus type 5 (AdHu5) and adeno-associated virus serotype 1 (AAV1) expressing a fusion protein of the pre-erythrocytic stage Plasmodium falciparum circumsporozoite protein (PfCSP) and the transmission-blocking sexual stage P25 protein (Pfs25). A two-dose heterologous AdHu5-prime/AAV1-boost immunization regimen proved to be highly effective for both full protection and transmission-blocking activity against transgenic P. berghei parasites expressing the corresponding P. falciparum antigens in mice. Remarkably, the immunization regimen induced antibody responses to both PfCSP and Pfs25 for over 9 months after the boosting and also maintained high levels of transmission-reducing activity (TRA: >99%) during that period, as evaluated by a direct feeding assay. If similar efficacies on P. falciparum can be shown following vaccination of humans, we propose that this multi-stage malaria vaccine regimen will be a powerful tool for malaria control, providing greater overall protection and cost-effectiveness than single-stage vaccines.

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“…Further highlighting the importance of specific Th2-cTfh targeting in vaccine optimization, the coadministration of viral vectored vaccines with RTS,S skewed the cTfh cell response toward Th1-cTfh cell activation, to the detriment of functional antibody induction and vaccine effi-cacy. 49 In contrast, multiple studies have shown that Th1-Tfh cells are associated with antibody induction to viral infections and vaccinations, including SARS-CoV-2, [16][17][18][19] highlighting that distinct vaccine approaches may be required for malaria vaccines compared to viral pathogens.…”

Section: Discussionmentioning

confidence: 99%

Th2-like T Follicular Helper Cells Promote Functional Antibody Production during Plasmodium falciparum Infection

Chan

Loughland

Rivera

et al. 2020

Cell Reports Medicine

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Summary CD4 + T follicular helper cells (Tfh) are key drivers of antibody development. During Plasmodium falciparum malaria in children, the activation of Tfh is restricted to the Th1 subset and not associated with antibody levels. To identify Tfh subsets that are associated with antibody development in malaria, we assess Tfh and antibodies longitudinally in human volunteers with experimental P. falciparum infection. Tfh cells activate during infection, with distinct dynamics in different Tfh subsets. Th2-Tfh cells activate early, during peak infection, while Th1-Tfh cells activate 1 week after peak infection and treatment. Th2-Tfh cell activation is associated with the functional breadth and magnitude of parasite antibodies. In contrast, Th1-Tfh activation is not associated with antibody development but instead with plasma cells, which have previously been shown to play a detrimental role in the development of long-lived immunity. Thus, our study identifies the contrasting roles of Th2 and Th1-Tfh cells during experimental P. falciparum malaria.

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CXCR3+ T Follicular Helper Cells Induced by Co-Administration of RTS,S/AS01B and Viral-Vectored Vaccines Are Associated With Reduced Immunogenicity and Efficacy Against Malaria

Cited by 36 publications

References 54 publications

Combination of RTS,S and Pfs25-IMX313 Induces a Functional Antibody Response Against Malaria Infection and Transmission in Mice

Combination of RTS,S and Pfs25-IMX313 Induces a Functional Antibody Response Against Malaria Infection and Transmission in Mice

A Viral-Vectored Multi-Stage Malaria Vaccine Regimen With Protective and Transmission-Blocking Efficacies

Th2-like T Follicular Helper Cells Promote Functional Antibody Production during Plasmodium falciparum Infection

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